PROJECT SUMMARY The study of yeast replicative aging has been instrumental in defining mechanistic aspects of aging, in identifying conserved eukaryotic aging genes, and has led to some of the best candidates for anti-aging drugs currently under development. However, the traditional micro-dissection lifespan assay is laborious and time consuming, making it impossible to perform large library screens of thousands of molecules. Here we propose to develop a novel high throughput method to systematically identify small molecules that delay aging, and to test the promising candidates in worms and in human cells. In Aim 1, we will develop a high-throughput method based on a novel genetic system and deep sequencing to measure the effect on lifespan of thousands of small molecules, including FDA approved drugs and the library of natural products. We will also screen small molecule drugs that target the human homologs of known yeast longevity genes. Small molecules identified to extend yeast lifespan in Aim 1 will be funneled into Aim 2, which describes efforts to determine (1) whether the drugs have conserved effects on aging using C. elegans, and (2) whether the drugs can ameliorate age-associated hallmarks in a human cell culture model of aging. Together these two aims will generate a set of drugs that set the stage for testing in mammals. The importance of expanding the repertoire of drugs that extend lifespan and delay aging cannot be underscored. Each new small molecule not only serves as a probe to define the mechanisms driving aging but also represents a new potential class of drugs that may extend human healthspan.